Luminal surface fabrication for cardiovascular prostheses

ABSTRACT

A method is provided for forming a mold surface with microscopic upstanding pillars for molding the inside surface of a vascular prostheses (synthetic blood vessel). The mold article is formed from a quantity of Teflon (polytetrafluoroethylene) which has a polished, flat surface on which a gold film has been sputter deposited. A photoresist layer, which cannot adhere directly to Teflon, adheres to the gold. The photoresist is exposed and developed leaving a sputter resistant mask defining the desired pillar locations, and the resulting workpiece is ion etched to form the pillars in the Teflon. A synthetic blood vessel material is cast against the Teflon mold to form blind recesses on the inside of the synthetic blood vessel, with the recesses being of predetermined uniform cross section and present in a predetermined uniform pattern.

ORIGIN OF INVENTION

The invention described herein was made in the performance of work undera NASA contract and is subject to the provisions of Section 305 of theNational Aeronautics and Space Act of 1958 Public Law 85-568 (72 Stat.435; USC 2457).

BACKGROUND OF THE INVENTION

More than 250,000 vascular replacement devices are implanted every yearin the United States alone. Most vascular prostheses are used to replacelarge internal diameter (over 6 mm) blood vessels such as in the aortaand major arteries, and currently available replacements are generallyconsidered satisfactory. However, small internal diameter (less than 6mm) vascular prostheses, such as those used for coronary arteries andperipheral vessels, suffer from low patency rates (they tend to beblocked). Recent efforts to develop suitable small diameter vascularprostheses have been hampered by an inability to find a material whichpromotes the development of a healthy neointima lining. If a propersurface is provided, such a lining is formed by the adsorption ofproteins in the blood onto the surface followed by platelet andleukocyte adherence and fibrin polymerization, resulting in growth of asurface layer which includes a layer of endothelial cells in directcontact with the blood. If the luminal lining overdevelops, thrombus(bloodclots) can occur. If the lining does not adhere well to the innersurface of the prosthesis, embolization can occur where all or part ofthe neointima detaches and can become trapped in small blood vessels.The surface morphology, or surface topography, of the implant, has beenshown to have a major effect on the adherence and development of theneointima lining.

Presently used techniques for forming the luminal surface ofcardiovascular prostheses involves the use of woven or smooth syntheticmaterials. There is no control of uniformity in the blood contactingsurfaces. A technique that allows for precise, tailor-made bloodcontacting surfaces would be of considerable value.

SUMMARY OF THE INVENTION

In accordance with one embodiment of the present invention, a syntheticblood vessel is provided, and a method for forming its internal surfaceis provided, wherein the internal surface has a closely-controlledmicrostructure which promotes the build up and firm attachment of aneointima lining thereto. A mold device against which the inner surfaceof the synthetic blood vessel is molded, includes a surface withmicroscopic upstanding pillars arranged in a predetermined pattern, withall pillars of a controlled geometry. The mold device can be formed ofTeflon (polytetrafluoroethylene) using photolithographic processes, bysputter depositing onto the Teflon a material such as gold, which aphotoresist can adhere to.

A photoresist is applied over the material on the Teflon and patternedto define the pillar locations. The patterned surface is then sputteretched using an ion beam resulting in the formation of upstandingpillars in areas protected by the photoresist.

The novel features of the invention are set forth with particularity inthe appended claims. The invention will be best understood from thefollowing description when read in conjunction with the accompanyingdrawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a perspective view of a synthetic blood vessel constructed inaccordance with the present invention.

FIG. 2 is a partial sectional view of the blood vessel of FIG. 1,showing the pattern of recesses in its inner surface.

FIG. 3 is a partial perspective view, showing the blood vessel of FIG. 1as it can be molded on a mandrell of the present invention.

FIG. 4 is an enlarged perspective view of a portion of the mandrell ofFIG. 3, showing the pattern of pillars on its molding surface.

FIGS. 5-9 are sectional views illustrating steps in the formation of thepattern of the mold device of FIG. 4.

FIG. 10 is a sectional view of an ion beam generator used in the processof FIG. 9.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

FIG. 1 illustrates a synthetic blood vessel prostheses 10 of the presentinvention, which has tubular walls 12 that form an inner surface 14 thatis to carry blood. The natural tendency of the blood is to try toincorporate the prostheses into the body by encapsulating it in livingtissue. The attempt to encapsulate includes the deposition of variouscomponents of the blood onto the prostheses surface 14. If all goeswell, healthy neointima lining is formed on the surface 14. It isimportant that the neointima lining be securely anchored to the innersurface 14, so that it does not later become detached and block adownstream smaller blood vessel. As shown in FIG. 2, the inner surface14 includes a large number of microscopic recesses 16 that each have aconsiderable depth with respect to their width, and which each have asubstantially constant cross section along their depth. Components ofblood can anchor themselves within the recesses 16 to prevent detachmentof a built up lining. The recesses 16 must have a small width ordiameter, in order that blood components can be anchored in it, but nottoo small or else blood components cannot easily flow into the recess. Adiameter on the order of 10 um (micrometers) is desirable. The sides ofthe recesses should be substantially perpendicular to the wall surface14, to resist washing away of blood components. The depth of therecesses should not be too great compared to the thickness T of theblood vessel walls in order to avoid substantial weakening of the bloodvessel walls. A recess depth about two to three times the recess widthis desirable. It is highly desirable that the configuration and patternof the recesses be easily controllable, so that a configuration andpattern that is found to be especially stable can be reproduced.

As shown in FIG. 3, the synthetic blood vessel 10 is constructed bymolding it, and particularly its inner surface 14, on a mold device 18such as a largely-cylindrical mandrel, which has a multiplicity ofupstanding pillars 22 extending from the mold surface 20.

FIG. 4 illustrates a portion of the surface 20 of the mold device,showing one configuration of the upstanding pillars 22 and of theirpattern. In one example, each pillar has a width of about 14 um, aheight H of about twice as much such as about 30 um, and hassubstantially the same hexagonal cross section along its entire height.

The mold device 18 is formed by a photolithographic process. In such aprocess, a layer of photoresist is applied to a mass of the moldmaterial. A photomask, with the prescribed pattern, is placed inintimate contact with the photoresist on the mold material. Areas of thephotoresist not covered by the pattern on the photomask are exposed tolight. The photoresist is then developed leaving the prescribed patternon the mold material. The mold with a pattern of photoresist is then ionetched to remove a depth of material except at the pillar areas, toleave pillars.

An ideal material for molding and or ion etching is Teflon (a trademarkof duPont de Nemours for polytetrafluoroethylene). Such material hasabout the lowest surface energy of any material so that almost nothingsticks to it, which aids in removing the mold from a molded product.This is especially important where long thin pillars are to be molded.Teflon has an especially high ion beam etch rate, relative to othermaterials. It may be noted that the etching process increases thematerial surface energy by microscopically roughening the surface andgenerating dangling bonds in the polymer, but the surface energy isstill relatively low. It would be possible to use a thin nickle meshmask through which to ion etch. However, it is difficult to maintainsuch a mask in intimate contact with the substrate being etched sincethe nickle mesh masks are very difficult to handle. It was found thatthe masks cracked and wrinkled from handling. In areas wheremask-substrate contact was poor, pattern resolution was lost and themask degraded due to heat from etching.

A major problem with the use of Teflon is that it is very difficult tomake a photoresist stick to the Teflon surface, because of the very lowsurface energy of Teflon. In accordance with one aspect of the presentinvention, applicant applies a layer of an intermediate material to theTeflon by energetically projecting submicroscopic particles of theintermediate material onto the Teflon surface to form a thin film. Thiscan be accomplished by sputter depositing a metal with a high ion etchrate such as gold onto the Teflon surface. FIG. 5 illustrates a portionof the mold device 18A prior to the formation of pillars therein, with athin layer 24 of metal such as gold applied to its surface 20A bysputter deposition.

A next step, shown in FIG. 6, is to apply a layer of photoresist 26 overthe sputtered-on gold layer 24. Photoresist can be applied in a uniformlayer by spinning the mold device with liquid photoresist on it, dippingthe mold device in photoresist, or spraying on a layer of photoresist,using well-known methods. A next step, shown in FIG. 7, is to apply aphotomask 30 lying facewise against the photoresist film 26, and todirect light, indicated at 31, through the mask to the photoresist. Thelight 31 is very well collimated to expose the photoresist with highdefinition. Either a positive or negative resist can be used, and acorresponding dark field or light field mask can be used. A particularmask 30 is shown as having opaque regions 32 where the pillars are to beformed, with the rest of the mask 33 being transparent. After thephotoresist is exposed, it is subjected to a developing process whichwashes away all of the photoresist except those areas 26B that definethe cross section of a pillar. The covered workpiece with pillar areascovered by photoresist areas 26B is shown in FIG. 8.

A next step, shown in FIG. 9, is to apply an energetic ion beam,indicated at 36, to etch the surface of the device so as to leave theupstanding pillars 22. The ion beam must be able to etch through thegold layer 24 and the desired depth of the mold material (such asTeflon) before it etches through the photoresist areas 26B and the goldlayer under it in order to produce upstanding pillars. Afterwards thephotoresist over each pillar can be dissolved as with acetone, and thegold dissolved by an acid. As discussed above, Teflon has a very highion beam etch rate, which greatly facilitates formation of tall pillars.Teflon is also useful because of its high chemical inertness, whichallows the removal of the photoresist 26B and the gold 24 withoutremoval of appreciable amounts of the Teflon. It is possible to useother materials, for the mold device, although difficulties areanticipated. it may be noted that the interpillar space 40 of the molddevice has a microstructure, that forms multiple steep (extending over45° from the horizontal) hills and valleys spaced apart on the order ofa micron which results from the ion beam sputtering, and the surface ofthe synthetic blood vessel molded from it has such multiple hills andvalleys spaced apart on the order of a micron. The Teflon mold devicewith the pillars therein, can be used to mold the inside surface of asmall (under 6 mm inside diameter) synthetic blood vessel in a number ofways such as by casting the synthetic blood vessel material around amold device mandrel and either expanding the blood vessel (withpressured gas) or contacting the mandrel. It may be noted that amaterial named Biomer is a preferred material for synthetic bloodvessels.

Applicant has formed microscopic pillars of the type shown in thedrawings by the method described above. The surface 20A (FIG. 5) of themold device 18A first had to be polished, to remove irregularities ofthe same order of magnitude as the pillars to be formed. The pillarspreferably have a width no more than about 25 microns. Polishing wasaccomplished by smoothing the surface and finally polishing it with 0.5um diamond grit. During polishing, care was taken to maintain the moldsurface flat, to assure that the mask later applied over the photoresistand gold would make good facewise contact with the photoresist.

The gold film 24 was applied by sputter depositing followed by anultrasonic cleaning and a rinse with ethanol. Gold is especially usefulbecause of its high sputter yield. In sputter depositing, an ion beam isdirected at a quantity of material to be deposited, to knock outparticles that are somewhat energetically deposited. Other materialsthat could be sputter deposited, and which have a high ion etch rate arecopper, gold and palladium, and brass. The sputtered-on particles havejust enough energy to penetrate the Teflon to a depth of a fewmolecules, to anchor themselves and provide a base for additionalparticles to build up a film on the Teflon. If very energetic particles(e.g., over 100 eV for most materials, or over 10 eV for Teflon) wereapplied, they would be implanted so deeply that they could not beremoved without damaging the pillars. Particle energies of under 1 eVcan readily build up securely onto Teflon. These particle energies areenergetic compared to techniques of electroplating or spinning onmaterials where the particle energies are substantially zero (much lessthan 0.01 eV). In ion beam etching, energies of over 100 eV are applied,typically to an inert gas.

The thickness of the gold layer 24 is important, with a thickness ofabout 0.3 um found to be satisfactory. If the gold film thickness ismuch less than that, such as less than about 0.15 um, then during theexposure of photoresist (FIG. 7), light passes through the photoresistand the gold layer, and is diffused by the Teflon and causes a "washout" or reduced resolution of the desired photoresist pattern created at26B. The gold film 24 should not be too thick, since the sputter etchrate of gold is considerably less than that of Teflon, which increasesthe time for ion etching. Also, a thicker gold layer may be more uneven,which could allow some of the pillars to be partially etched away beforethe interpillar areas have been removed to the desired depth.Accordingly, it is preferred that the thickness of the gold film be lessthan 3 microns in thickness.

In some experiments, applicant has applied a positive resist, byapplying Shipley Microposit, and has applied a negative photoresist byapplying Kodak Micro Resist 752. It may be noted that both of thesephotoresists will either run off or bead upon a bare Teflon surface.These resists were chosen because they each have a very high resistanceto ion etching. Layers of photoresist of these materials in a thicknessof about 0.4 um were applied over the gold. After ion beam etchingthrough the 0.3 um gold film and about 20 um of Teflon, the thickness ofthe photoresist layers decreased from about 0.4 um to about 0.15 um.

The ion beam used to sputter etch the targets was generated by an argonion source shown in FIG. 10. Argon gas was admitted to the sourcethrough a gas inlet 44 to the region of a cathode filament 46. An anode48 was maintained at a potential of about 40 volts with respect to thecathode, to draw electrons from the cathode. A coil 50 applied amagnetic field of about 50 Gauss to increase the pathlength of theelectrons, to thereby increase the plasmac density in a region behind ascreen grid 50. The screen grid was a few tens of volts below the plasmapotential to extract ions to form an ion beam. The ion beam wasaccelerated by an accelerator grid 52 maintained at a voltage between1,000 and 2,000 volts with respect to the screen grid 50, to produce ionbeam energies ranging from 1,000 to 2,000 eV, with beam currentdensities ranging from 0.25 to 0.7 mA/cm² at the target. The Teflon wasseparated by about 15 cm from the accelerator grid 52. The ion beamdivergence angle was approximately 10°. The Teflon targets were rotatedunder the beam to minimize the effects of any ion beam non-uniformity.The ion beam was applied for about 15 minutes to produce pillars of aheight of about 40 um and width of about 14 um, in a pattern containingabout 64,500 pillars in an area of 6.5 cm².

Thus, the invention provides a method and apparatus for producing acardiovascular prostheses which has a multiplicity of microscopic blindholes on its luminal surface. A mold device is formed with multiplepillars, and the cardiovascular prostheses is molded or cast against thepillared surface to form a pattern of deep but blind holes in theprostheses into which blood particles can anchor themselves to form aneointima lining which will not break free. The pillars are formed byion etching a Teflon mold device with the pillar areas protected by aphotoresist that is highly resistant to ion etching (at least ten timesas resistant as the Teflon workpiece) applied by lithographic methods.The photoresist is bonded to the Teflon surface by an easily sputteretched intermediate layer which was sputter deposited onto the Teflonsurface.

Although particular embodiments of the invention have been described andillustrated herein, it is recognized that modifications and variationsmay readily occur to those skilled in the art, and consequently, it isintended that the claims be interpreted to cover such modifications andequivalents.

What is claimed is:
 1. A synthetic blood vessel device comprising:atubular structure having an internal surface containing a multiplicityof blind holes, each hole having a depth greater than its width, and asubstantially constant cross section along its depth, and most of saidholes being substantially identical in cross section.
 2. The devicedescribed in claim 1 wherein:said internal surface has a diameter ofless than 6 millimeters, and said holes each have a width no more thanabout 25 microns.
 3. A synthetic blood vessel comprising:a tubularstructure having an internal surface and forming a multiplicity of blindholes in said surface, each of said holes having a width on the order of10 micrometers and the holes having walls substantially perpendicular tosaid internal surface along most of the depths of said holes.
 4. Thesynthetic blood vessel described in claim 3 wherein:said internalsurface has a microstructure forming multiple steep hills and valleysspaced apart on the order of a micron.